Multi-armed polymers comprising free-radical-polymerizable monomers and compositions, systems and methods pertaining to the same

ABSTRACT

In some aspects, the present disclosure pertains to multi-arm polymers that comprise a core, a plurality of polymer segments having a first end that is covalently attached to the core and a second end comprising a moiety that comprises a reactive group, wherein the polymer segments comprise one or more free-radical-polymerizable monomers. In some aspects, systems are provided that comprise a first composition comprising such a multi-arm polymer and a second composition comprising a multifunctional compound that comprises functional groups that are reactive with the reactive groups of the multi-arm polymer. In some aspects, systems are provided that comprise crosslinked reaction products of such a multi-arm polymer and such a multifunctional compound.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.62/892,786, entitled “MULTI-ARMED POLYMERS COMPRISINGFREE-RADICAL-POLYMERIZABLE MONOMERS AND COMPOSITIONS, SYSTEMS ANDMETHODS PERTAINING TO THE SAME” and filed Aug. 28, 2019, the entiredisclosure of which is incorporated herein by reference.

FIELD

The present disclosure relates to multi-armed polymers, compositionscontaining the multi-armed polymers, methods of making multi-armedpolymers, and methods of using multi-armed polymers, among otheraspects. The multi-armed polymers of the present disclosure are useful,for example, in various biomedical applications.

BACKGROUND

Bioerodible injectable hydrogels are a newly emerging class of materialshaving a variety of medical uses.

As one specific example, in the case of SpaceOAR®, a long-termbioerodible injectable hydrogel based on multi-arm PEG-based, suchproducts are used to create or maintain space between tissues in orderto reduce side effects of off-target radiation therapy. See“AugmenixAnnounces Positive Three-year SpaceOAR Clinical Trial Results,” ImagingTechnology News, Oct. 27, 2016. As another specific example, Augmenixhas developed TraceIT® Hydrogel, a bioerodible injectable hydrogelsynthetic hydrogel consisting primarily of water and iodinatedcross-linked polyethylene glycol (PEG) that is visible under CT, conebeam, ultrasound and MR imaging and is useful as a tissue marker (e.g.,for targeted radiation therapy). See“Augmenix Receives FDA Clearance toMarket its TraceIT™ Tissue Marker,” BusinessWire Jan. 28, 2013. TraceIT®hydrogel remains stable and visible in tissue for three months, longenough for radiotherapy, after which it is absorbed and cleared from thebody. Id.

There is a continuing need in the biomedical arts for additionalhydrogels, including bioerodible injectable hydrogels, for precursors ofsuch hydrogels, for methods of making such hydrogels and precursors, formethods of using such hydrogels and precursors, and for systems forforming such hydrogels, among other needs.

SUMMARY

In some aspects, the present disclosure pertains to multi-arm polymersthat comprise a core, a plurality of polymer segments having a first endthat is covalently attached to the core and a second end comprising amoiety that comprises a reactive group, wherein the polymer segmentscomprise one or more free-radical-polymerizable monomers.

In some embodiments, the polymer segments comprise one or morehydrophilic aprotic monomers. For example, the polymer segments maycomprise one or more monomers selected from N-vinyl pyrrolidone,hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl etheracrylate and PEG methyl ether methacrylate, among many others.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the core of the multi-arm polymers may be apolyol residue core.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the reactive groups are electrophiles. Forexample, the reactive groups may be selected from N-hydroxysuccinimideesters, imidazole esters, imidazole carboxylates and benzotriazoleesters, among other possibilities.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the reactive groups may be nucleophiles. Forexample, the reactive groups may be amine groups or thiol groups, amongother possibilities.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the moiety that comprises a reactive group mayfurther comprise a hydrolysable ester group.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the moiety that comprises a reactive group maycomprise a diester. For example, the diester may be selected from amalonic-acid-based diester, a succinic-acid-based diester, aglutaric-acid-based diester and an adipic-acid-based diester, amongothers.

In other aspects, systems are provided that comprise (a) a firstcomposition comprising a multi-arm polymer in accordance with the aboveaspects and embodiments and (b) a second composition comprising amultifunctional compound that comprises functional groups that arereactive with the reactive groups of the multi-arm polymer.

In some embodiments, the reactive groups of the multi-arm polymer may beselected from one of electrophilic groups and nucleophilic groups andthe functional groups of the multifunctional compound may be selectedfrom the other of the electrophilic groups and the nucleophilic groups.For instance, in certain embodiments, the reactive groups may beelectrophilic groups, for example, N-hydroxysuccinimide ester groups,among many others, and the functional groups may be nucleophilic groups,for example, amine groups or thiol groups, among many others.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the second composition comprises a polyamine.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the polyamine comprises three or more aminegroups.

In some embodiments, which can used in conjunction with the aboveaspects and embodiments, the system may further comprise a deliverydevice. For example, the delivery device may comprises a first reservoircontaining the first composition and a second reservoir containing thesecond composition.

In still other aspects, the present disclosure provides crosslinkedreaction products of (a) a multi-arm polymer in accordance with theabove aspects and embodiments and (b) a multifunctional compound inaccordance with the above aspects and embodiments.

In addition to the above, further aspects and embodiments of the presentdisclosure will become readily apparent upon review of the DetailedDescription to follow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a method of making a reactivemulti-arm polymer, in accordance with an embodiment of the presentdisclosure.

FIG. 2 is a schematic illustration of a method crosslinking a reactivemulti-arm polymer with a multifunctional crosslinking agent, inaccordance with an embodiment of the present disclosure.

FIG. 3A is a schematic illustration of a method of forming a multi-armpoly(vinyl pyrrolidone) polymer having terminal RAFT polymerizationgroups, in accordance with an embodiment of the present disclosure.

FIG. 3B is a schematic illustration of a method of forming a multi-armpoly(vinyl pyrrolidone) terminated with reactive succinimidyl glutarategroups, in accordance with an embodiment of the present disclosure.

DETAILED DESCRIPTION

In various aspects, the present disclosure pertains to methods in whichpolymerization of at least one type of unsaturated,free-radical-polymerizable monomer proceeds from a suitablemultifunctional initiator molecule.

Unsaturated free-radical-polymerizable monomers for use in the presentdisclosure may be selected from the following unsaturated monomers,among others: (a) vinyl monomers, including vinyl pyrrolidone, vinylalcohol, halogenated vinyl compounds such as vinyl chloride and vinylfluoride, vinyl imidazole, vinyl ethers, vinyl esters such as vinylacetate, acrylonitrile, and vinyl aromatic monomers such as substitutedand unsubstituted styrene, (b) alkylene monomers and derivatives, suchas ethylene, propylenes (e.g., α-propylene, isopropylene), butylenes(e.g., α-butylene, β-butylene, isobutylene), pentenes, etc., (c)fluorinated unsaturated monomers including fluorinated alkylene monomers(e.g., tetrafluoroethylene, trifluorochloroethylene, vinylidenefluoride, etc.), (d) (meth)acrylic monomers and derivatives, such asacrylic acid, methacrylic acid, methyl acrylate, methyl methacrylate,ethyl acrylate, ethyl methacrylate, butyl acrylate, butyl methacrylate,hydroxyethyl acrylate, hydroxyethyl methacrylate, glyceryl acrylate,glyceryl methacrylate, dimethylaminoethyl acrylate, dimethylaminoethylmethacrylate, PEG acrylates and PEG methacrylates, for example, PEGmethyl ether acrylate and PEG methyl ether methacrylate, acrylamide,methacrylamide, ethacrylamide, and so forth, (e) nitriles includingacrylonitrile, and methacrylonitrile, and (f) diene monomers such as1,3-butadiene, chloroprene, and isoprene, as well as combinations of theforegoing monomers.

In particular embodiments, the unsaturated free-radical-polymerizablemonomers are selected from monomers which are hydrophilic, aprotic,biologically well-tolerated and can be polymerized via a livingpolymerization reaction mechanism, which allows for controlled polymerarchitecture. Specific examples of such unsaturatedfree-radical-polymerizable monomers include N-vinyl pyrrolidone,hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl etheracrylate and PEG methyl ether methacrylate, among others.

In various embodiments, reverse-addition fragmentation transfer (RAFT)polymerization of the at least one type of unsaturatedfree-radical-polymerizable monomer is conducted. In these embodiments,the multifunctional initiator molecule may comprise a multifunctionalcore having a plurality of reverse-addition fragmentation transfer(RAFT) polymerization groups. Examples of RAFT polymerization groupsinclude thiocarbonylthio groups

In certain embodiments, the RAFT polymerization groups may comprisedithioester groups, trithiocarbonate groups, dithiocarbonate groups(including O-esters of dithiocarbonate (xanthates) such as ethylxanthate), dithiocarbamate groups, and dithiobenzoate groups.

In certain embodiments of the disclosure, a multifunctional initiatormolecule may be formed by a method comprising coupling a plurality ofRAFT polymerization groups to a polyol molecule. For instance, amultifunctional initiator molecule may be formed by a method comprisingcondensing a polyol with a compound that comprises a carboxyl group andthiocarbonylthio group or reacting a polytosylate and xanthate. Specificexamples of such compounds include4-cyano-4-(phenylcarbonothioylthio)pentanoic acid,4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, and2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid, among others.In other embodiments, RAFT polymerization groups may be coupled to apolyol molecule by, for example, amide coupling, Diels-Alder couplingreactions, and so forth.

Illustrative polyols for use in forming alkoxyamine molecules include,for example, straight-chained, branched and cyclic aliphatic polyolsincluding straight-chained, branched and cyclic polyhydroxyalkanes,straight-chained, branched and cyclic polyhydroxy ethers and polyhydroxypolyethers, straight-chained, and branched and cyclic polyhydroxyalkylethers and polyhydroxyalkyl polyethers, straight-chained, branched andcyclic sugars and sugar alcohols, such as glycerol, mannitol, sorbitol,inositol, xylitol, quebrachitol, threitol, arabitol, erythritol,adonitol, dulcitol, fucose, ribose, arabinose, xylose, lyxose, rhamnose,galactose, glucose, fructose, sorbose, mannose, pyranose, altrose,talose, tagatose, pyranosides, sucrose, lactose, or maltose, oligomers(defined herein as ranging from two to ten units, including dimers,trimers, tetramers, pentamers, hexamers, heptamers, octamers, enneamersor decamers) and polymers (defined herein as eleven or more units) ofstraight-chained, branched and cyclic sugars and sugar alcohols,including the preceding sugars and sugar alcohols, starches, amylose,dextrins, cyclodextrins, polyhydroxy crown ethers, or polyhydroxyalkylcrown ethers, and aromatic polyols including1,1,1-tris(4′-hydroxyphenyl) alkanes, such as1,1,1-tris(4-hydroxyphenyl)ethane, and 2,6-bis(hydroxyalkyl)cresols,among others. In certain embodiments, the polyol is an oligomer of asugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol,or erythritol. In certain embodiments, a polyol may be selected whichcontains two or more hydroxyl groups, for example, between 4 and 12hydroxyl groups in certain instances.

In some embodiments, polymerization of at least one type of unsaturated,free-radical-polymerizable monomer from a suitable multifunctionalinitiator molecule may be enhanced by conducting the polymerization inthe presence of a radical initiator. Examples of radical initiatorsinclude, for example, hydrogen peroxide, organic peroxides such asdi-t-butyl peroxide, benzoyl peroxide or methyl ethyl ketone peroxide,among others, and azo compounds such as azobisisobutyronitrile (AIBN),or 1,1′-azo-bis(cyclohexane-carbonitrile) (ABCN), among others.

Using the above and other techniques, a multi-arm polymer (e.g., onehaving 2, 3, 4, 5, 6, 7, 8, 9, 10 or more arms) with RAFT polymerizationend-groups can be formed. Using the above and other techniques, amulti-arm polymer that comprises a core (e.g., a residue of a polyol)and a plurality of polymer segments, each having a first end and asecond end, and each formed from polymerization of at least one type ofunsaturated free-radical-polymerizable monomer, wherein the first end islinked to the core and the second end is linked to RAFT polymerizationgroup can be formed.

After polymerization, in various embodiments, the RAFT polymerizationgroups may be removed to form, for example, a hydroxy-terminatedmulti-armed polymer. In various embodiments, the RAFT polymerizationgroups may be removed, for example, through nucleophilic substitution.

Although the process described above employs RAFT polymerization, othertypes of polymerization may be used for forming multi-arm polymers aswell. As one example, such multi-arm polymers can be formed bynitroxide-mediated polymerization (NMP) of at least one type ofunsaturated free-radical-polymerizable monomer, for instance, whereinthe polymerization proceeds from a multifunctional initiator moleculehaving multiple nitroxide groups as described in copending Ser. No.62/892,782. As another example, such multi-arm polymers can be formed byatom transfer radical polymerization (ATRP) of at least one type ofunsaturated free-radical-polymerizable monomer, for instance, whereinthe polymerization proceeds from a multifunctional initiator moleculehaving multiple alkyl halide groups in the presence of a coppercatalyst. Where RAFT is used to form the polymer segments, the polymerproducts may be identified by a measurable amount of residual sulfur.Where NMP is used to form the polymer segments, the polymer products maybe identified by a measurable amount of nitroxide radicals. Where ATRPis used to form the polymer segments, the polymer products may beidentified by a measurable amount of copper.

The formation of such multi-arm polymers is shown schematically in FIG.1, in which a core molecule 110 (e.g., a polyol core, among otherpossibilities) is used to form a multifunctional initiator moleculehaving a multiple polymerization groups 120 (e.g., an initiator moleculecomprising multiple RAFT polymerization groups, multiple NMPpolymerization groups, or multiple ATRP polymerization groups).Subsequently, polymerization of a suitable unsaturatedfree-radical-polymerizable monomer 125 (e.g., vinyl pyrrolidone, amongmany others) proceeds from the multifunctional initiator molecule toform a multi-arm polymer that comprises a core 110 (e.g., a polyolresidue, among others) and a plurality of polymer segments 130, eachhaving a first end and a second end, wherein the first end is linked tothe core 110. In the embodiment shown, the second end of each polymersegment 130 comprises a polymerization group 120 (e.g., a RAFTpolymerization group).

In various embodiments, a reactive multi-arm polymer that comprises acore and a plurality of polymer segments, each having a first end and asecond end, and each formed from at least one type of unsaturatedfree-radical-polymerizable monomer may be formed, wherein the first endis linked to the core and the second end comprises a reactive group. Forexample, as shown schematically in FIG. 1, a reactive group 140 may beprovided at the second end of each polymer segment 130. In certainembodiments, the second end comprises a hydrolysable ester grouppositioned between the reactive group and the polymer segment. As above,where RAFT is used to form the polymer segments, the reactive multi-armpolymer may be identified by a measurable amount of residual sulfur,where NMP is used to form the polymer segments, the reactive multi-armpolymer may be identified by a measurable amount of nitroxide radicals,and where ATRP is used to form the polymer segments, the reactivemulti-arm polymer may be identified by a measurable amount of copper.

The reactive groups of the reactive multi-arm polymer may be, forexample, electrophilic groups or nucleophilic groups. In certainembodiments, the reactive groups of the reactive multi-arm polymer maybe electrophilic groups selected from imidazole esters, imidazolecarboxylates, benzotriazole esters, and imide esters, includingN-hydroxysuccinimidyl esters. In certain embodiments, the reactivegroups of the reactive multi-arm polymer may be nucleophilic groupsselected from amine groups and thiol groups.

In particular embodiments, a reactive multi-arm polymer may be formed byreacting (a) a polymer that comprises a core (e.g., a polyol residue,among others) and a plurality of polymer segments, each having a firstend and a second end, formed from at least one type of unsaturatedfree-radical-polymerizable monomer, wherein the first end is linked tothe core and the second end comprises a hydroxyl group with (b) a cyclicanhydride (e.g., glutaric anhydride, succinic anhydride, malonicanhydride, etc.) to form a reaction product (c) in the form of a polymerthat comprises the core and the plurality of polymer segments, whereinthe first end of the polymer segment is linked to the core and thesecond end comprises moiety that comprises a carboxylic acid group and ahydrolysable ester group positioned between the carboxylic acid groupand the polymer segment. Subsequently, the reaction product (c) may betreated with a coupling agent (e.g., a carbodiimide coupling agent suchas N,N′-dicyclohexylcarbodiimide (DCC),1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),N-Hydroxybenzotriazole (HOBt), BOP reagent, and/or another couplingagent) and N-hydroxysuccinimide (NHS), to yield a multi-arm polymercomprising succinimidyl end groups, in particular, a multi-arm polymerthat comprises the core and the plurality of polymer segments, whereinthe first end of the polymer segments is linked to the core and thesecond end comprises a moiety that comprises a hydrolysable ester groupand a succinimide ester group.

In a specific example illustrated schematically in FIG. 3A, hexaglycerol(a polyol having 8 hydroxyl groups) is condensed with4-cyano-4-(phenylcarbonothioylthio) pentanoic acid to form amultifunctional initiator comprising multiple RAFT polymerizationgroups. See, e.g., Wei, Z., Hao, X., Gan, Z., Hughes, T. C., “One-potsynthesis of hyperbranched glycopolymers by RAFT polymerization,”Journal of Polymer Science Part A: Polymer Chemistry 2012, 50 (12),2378-2388. Subsequently, an unsaturated free-radical-polymerizablemonomer (N-vinyl pyrrolidone) is added together with a radical initiator(AIBN), and the mixture allowed to react to form 8-arm PVP in which thePVP segments are terminated with RAFT polymerization groups. Then, asillustrated schematically in FIG. 3B (which is a continuation of FIG.3A), the thiocarbonothio groups of the 8-arm PVP are removed throughnucleophilic substitution and succinimidyl glutarate groups are addedusing glutaric anhydride and N-hydroxysuccinide as reagents. See, e.g.,Willcock, H., O'Reilly, R. K., “End group removal and modification ofRAFT polymers,” Polym. Chem. 2010, 1(2), 149-157 and Lopez-Perez, P. M.,da Silva, R. M. P., Strehin, I., Kouwer, P. H. J., Leeuwenburgh, S. C.G.; Messersmith, P. B., “Self-healing hydrogels formed by complexationbetween calcium ions and bisphosphonate-functionalized star-shapedpolymers,” Macromolecules 2017, 50 (21), 8698-8706.

Reactive multi-arm polymers formed as described above may be watersoluble. Moreover, reactive multi-arm polymers formed as described abovemay be crosslinked with a suitable crosslinking agent, either in vivo orex vivo, to form a crosslinked hydrogel.

In certain embodiments, the reactive multi-arm polymer may becrosslinked with a multifunctional compound having functional groupsthat are reactive with the reactive groups of the multi-arm polymer. Forexample, in some embodiments, the reactive groups of the reactivemulti-arm polymer are nucleophilic groups and the functional groups ofthe multifunctional compound group are electrophilic groups. In someembodiments, the reactive groups of the reactive multi-arm polymer areelectrophilic groups and the functional groups of the multifunctionalcompound are nucleophilic groups. For example, the functional groups ofthe multifunctional compound may be electrophilic groups selected fromimidazole esters, imidazole carboxylates, benzotriazole esters, andimide esters, including N-hydroxysuccinimidyl esters. As anotherexample, the functional groups of the multifunctional compound may benucleophilic groups selected from amine groups and/or thiol groups.

In some embodiments, the reactive groups of the reactive multi-armpolymer and the functional groups of the multifunctional compound reactwith one another via an amide coupling reaction.

In various aspects, the present disclosure pertains to a crosslinkablesystem comprising (a) a first composition comprising a reactivemulti-arm polymer like that described above, which comprises a core(e.g., a polyol residue, among others) and a plurality of polymersegments, each having a first end and a second end, and each formed fromat least one type of unsaturated free-radical-polymerizable monomer,wherein the first end is linked to the core and the second endcomprising a moiety that comprise a reactive group and, optionally, ahydrolysable ester group that is positioned between the reactive groupand the polymer segment and (b) a second composition comprising amultifunctional compound like that described above, which comprisesfunctional groups that are reactive with the reactive groups. In someembodiments, the reactive groups of the reactive multi-arm polymer areelectrophilic groups and the functional groups of the multifunctionalcompound are nucleophilic groups. In some embodiments, the reactivegroups of the reactive multi-arm polymer and the functional groups ofthe multifunctional compound react with one another via an amidecoupling reaction.

In addition to the reactive multi-arm polymer, the first composition mayfurther comprise, for example, therapeutic agents and/or contrastagents, among other possibilities. In addition to the multifunctionalcompound, the second composition may further comprise, for example,therapeutic agents and/or contrast agents, among other possibilities.

In various embodiments, the system will include one or more deliverydevices for delivering the first and second fluid compositions to asubject. For example, the system may include a delivery device thatcomprises a first reservoir that contains the first composition (e.g., afirst liquid composition comprising the reactive multi-arm polymer, or afirst dry composition that comprises the reactive multi-arm polymercompound, to which a suitable fluid such as water for injection, saline,etc. can be added to form a fluid composition) and a second reservoirthat contains the second composition (e.g., a second fluid compositioncomprising the multifunctional compound, or a second dry compositionthat comprises the multifunctional compound, to which a suitable fluidsuch as water for injection, saline, etc. can be added to form a fluidcomposition). During operation, the first and second compositions aredispensed from the first and second reservoirs, whereupon the first andsecond compositions interact and crosslink with one another to form ahydrogel.

In particular embodiments, the system may include a delivery device thatcomprises a double-barrel syringe, which includes first barrel having afirst barrel outlet, which first barrel contains the first fluidcomposition, a second barrel having a second barrel outlet, which secondbarrel contains the second fluid composition, a first plunger that ismovable in first barrel, and a second plunger that is movable in secondbarrel.

In some embodiments, the device may further comprise a mixing sectionhaving a first mixing section inlet in fluid communication with thefirst barrel outlet, a second mixing section inlet in fluidcommunication with the second barrel outlet, and a mixing sectionoutlet. In some embodiments, the device may further comprise a cannulaor catheter tube that is configured to receive the first and secondfluid compositions from the first and second barrels. For example, acannula or catheter tube may be configured to form a fluid connectionwith an outlet of a mixing section by attaching the cannula or cathetertube to an outlet of the mixing section, for example, via a suitablefluid connector such as a luer connector.

As another example, the catheter may be a multi-lumen catheter thatcomprise a first lumen and a second lumen, a proximal end of the firstlumen configured to form a fluid connection with the first barrel outletand a proximal end of the second lumen configured to form a fluidconnection with the second barrel outlet. In some embodiments, themulti-lumen catheter may comprise a mixing section having a first mixingsection inlet in fluid communication with a distal end of the firstlumen, a second mixing section inlet in fluid communication with adistal end of the second lumen, and a mixing section outlet.

During operation, when the first and second plungers are depressed, thefirst and second fluid compositions are dispensed from the first andsecond barrels, whereupon the first and second fluid compositionsinteract and crosslink to form a hydrogel, which is administered onto orinto tissue of a subject. For example, the first and second fluidcompositions may pass from the first and second barrels, into the mixingsection via first and second mixing section inlets, whereupon the firstand second fluid compositions are mixed to form an admixture, whichadmixture exits the mixing section via the mixing section outlet. Insome embodiments, a cannula or catheter tube is attached to the mixingsection outlet, allowing the admixture to be administered to a subjectafter passing through the cannula or catheter tube.

As another example, the first fluid composition may pass from the firstbarrel outlet into the first lumen of a multi-lumen catheter and thesecond fluid composition may pass from the second barrel outlet into thesecond lumen of the multi-lumen catheter. In some embodiments the firstand second fluid compositions may pass from the first and second lumeninto a mixing section at a distal end of the multi-lumen catheter viafirst and second mixing section inlets, respectively, whereupon thefirst and second fluid compositions are mixed in the mixing section toform an admixture, which admixture exits the mixing section via themixing section outlet.

In additional aspects, the present disclosure pertains to crosslinkedproducts of (a) a reactive multi-arm polymer like that described above,which comprises a core and a plurality of polymer segments, each havinga first end and a second end, and each formed from at least one type ofunsaturated free-radical-polymerizable monomer, wherein the first end islinked to the core and the second end comprising a moiety that comprisea reactive group and, optionally, a hydrolysable group that ispositioned between the reactive group and the polymer segment and (b) amultifunctional compound like that above, which comprises functionalgroups that are reactive with the reactive groups. Such crosslinkedproducts may be formed in vivo (e.g., using a delivery device like thatdescribed above), or such crosslinked products may be formed ex vivo andsubsequently administered to a subject.

In various embodiments, the reaction products of the functional groupsof the multifunctional compound with the reactive groups of the reactivemulti-arm polymer comprise amide linkages.

In certain beneficial embodiments, the reactive groups of the reactivemulti-arm polymers for use in the first compositions of the abovesystems and devices and for use in forming the above crosslinkedproducts (i.e., crosslinked products of the multi-arm polymers describedherein with the multifunctional compounds as described herein), may beselected from imidazolyl esters, benzotriazole esters, imide esters,including N-hydroxysuccinimidyl esters, and imidazolyl carboxylates,among others.

In various embodiments, the multifunctional compound for use in thesecond compositions of the above systems and devices, and for use informing the above crosslinked products, may be a polyamine. In general,polyamines suitable for use in the present disclosure include, forexample, small molecule polyamines (e.g., containing at least two aminegroups, for instance, from 3 to 20 amine groups in certain embodiments),comb polymers having amine side groups, and branched polymers havingamine end groups, including dendritic polymers having amine end groups.

Particular examples of multifunctional amines which may be used as themultifunctional compound include trilysine, ethylenetriamine, diethylenetriamine, hexamethylenetriiamine, di(heptamethylene) triamine,di(trimethylene) triamine, bis(hexamethylene) triamine, triethylenetetramine, tripropylene tetramine, tetraethylene pentamine,hexamethylene heptamine, pentaethylene hexamine, dimethyl octylamine,dimethyl decylamine, and JEFFAMINE polyetheramines available fromHuntsman Corporation, among others. Further particular examples ofmultifunctional amines include polypeptides including poly(L-lysine),chitosan, and poly(allyl amine), among others.

As shown schematically in FIG. 2, a reactive multi-arm polymer 210 likethat described above (e.g., comprising a core and a plurality of PVPsegments, each PVP segment terminated with a succinimidyl-group) iscrosslinked with a multifunctional compound 220 comprising functionalgroups that are reactive with the reactive groups of the multi-armpolymer 210 (e.g., a polyamine such as trilysine) to form a crosslinkedproduct 230.

Compositions comprising the multi-arm polymers as described herein, aswell as compositions comprising the cross-linked polymers describedherein (i.e., crosslinked products of the multi-arm polymers describedherein with the multifunctional compounds as described herein), can beused in a wide variety of biomedical applications, including medicaldevices, implants, and pharmaceutical compositions.

In various embodiments, compositions can be formed that include themulti-arm polymers described herein as well as one or more additionalagents. In various embodiments, compositions can be formed that includethe cross-linked polymers described herein as well as one or moreadditional agents.

Examples of such additional agents include therapeutic agents andimaging agents, among others.

Examples of imaging agents include (a) fluorescent dyes such asfluorescein, indocyanine green, or fluorescent proteins (e.g. green,blue, cyan fluorescent proteins), (b) contrast agents for use inconjunction with magnetic resonance imaging (MRI), including contrastagents that contain elements that form paramagnetic ions, such asGd^((III)), Mn^((II)), Fe^((III)) and compounds (including chelates)containing the same, such as gadolinium ion chelated withdiethylenetriaminepentaacetic acid, (c) contrast agents for use inconjunction with ultrasound imaging, including organic and inorganicechogenic particles (i.e., particles that result in an increase in thereflected ultrasonic energy) or organic and inorganic echolucentparticles (i.e., particles that result in a decrease in the reflectedultrasonic energy), (d) contrast agents for use in connection with x-rayfluoroscopy, including metals and metal compounds (e.g., metal salts,metal oxides, etc.), for instance, barium compounds, bismuth compoundsand tungsten, among others, and iodinated compounds, among others, (e)radiocontrast agents, such as those based on the clinically importantisotope ^(99m)Tc, as well as other gamma emitters such as ¹²³I, ¹²⁵I,¹³¹I, ¹¹¹In, ⁵⁷Co, ¹⁵³Sm, ¹³³Xe, ⁵¹Cr, ^(81m)Kr, ²⁰¹Tl, ⁶⁷Ga, and ⁷⁵Se,among others, (f) positron emitters, such as ¹⁸F, ¹¹C, ¹³N, ¹⁸O, and⁶⁸Ga, among others, may be employed to yield functionalized radiotracercoatings, and (g) contrast agents for use in connection withnear-infrared (NIR) imaging, which can be selected to impartnear-infrared fluorescence to the coatings of the present disclosure,allowing for deep tissue imaging and device marking, for instance,NIR-sensitive nanoparticles such as gold nanoshells, carbon nanotubes(e.g., nanotubes derivatized with hydroxyl or carboxyl groups, forinstance, partially oxidized carbon nanotubes), dye-containingnanoparticles, such as dye-doped nanofibers and dye-encapsulatingnanoparticles, and semiconductor quantum dots, among others.NIR-sensitive dyes include cyanine dyes, squaraines, phthalocyanines,porphyrin derivatives and borondipyrromethane (BODIPY) analogs, amongothers.

Compositions in accordance with the present disclosure includelubricious compositions for medical applications, compositions fortherapeutic agent release (e.g., by including one or more therapeuticagents in a matrix of the crosslinked polymers, by using the crosslinkedpolymers to encapsulate one or more therapeutic agents, etc.), implants,which may be formed ex vivo or in vivo (e.g., compositions for use astissue markers, compositions that act as spacers to reduce side effectsof off-target radiation therapy, cosmetic compositions, etc.).

What is claimed is:
 1. A system comprising (a) a first compositioncomprising a multi-arm polymer comprising a core, a plurality of polymersegments having a first end that is covalently attached to the core anda second end comprising a moiety that comprises a reactive group, (b) asecond composition comprising a multifunctional compound that comprisesfunctional groups that are reactive with the reactive group of themulti-arm polymer, and (c) a delivery device that comprises a firstreservoir containing the first composition and a second reservoircontaining the second composition.
 2. The system of claim 1, wherein thereactive group is selected from one of an electrophilic group and anucleophilic group and wherein the functional groups are selected fromthe other of the electrophilic group and the nucleophilic group.
 3. Thesystem of claim 1, wherein the reactive group is an electrophilic groupand the functional groups are nucleophilic groups.
 4. The system ofclaim 3, wherein the nucleophilic groups are selected from amine groupsand thiol groups.
 5. The system of claim 3, wherein the secondcomposition comprises a polyamine.
 6. The system of claim 5, wherein thepolyamine comprises three or more amine groups.
 7. The system of claim1, wherein the delivery device comprises a catheter.
 8. The system ofclaim 7, wherein the catheter is a multi-lumen catheter.
 9. The systemof claim 8, wherein the device further comprises a mixing section havinga first mixing section inlet in fluid communication with a distal end ofa first lumen, a second mixing section inlet in fluid communication witha distal end of a second lumen, and a mixing section outlet.
 10. Asystem comprising (a) a first composition comprising a multi-arm polymercomprising a core, a plurality of polymer segments having a first endthat is covalently attached to the core and a second end comprising amoiety that comprises a reactive group, the polymer segments comprisingone or more free-radical-polymerizable monomers, (b) a secondcomposition comprising a multifunctional compound that comprisesfunctional groups that are reactive with the reactive group of themulti-arm polymer, and (c) a delivery device that comprises a firstreservoir containing the first composition and a second reservoircontaining the second composition.
 11. The system of claim 10, whereinthe one or more unsaturated free-radical-polymerizable monomers compriseone or more hydrophilic, aprotic, unsaturated free-radical-polymerizablemonomers.
 12. The system of claim 10, wherein the core is a polyolresidue core, wherein the reactive group is an electrophile, and whereinthe second composition comprises a polyamine.
 13. The system of claim10, wherein the reactive group is selected from N-hydroxysuccinimideesters, imidazole esters, imidizole carboxylates and benzotriazoleesters.
 14. The system of claim 10, wherein the moiety that comprises areactive group comprises a hydrolysable ester group.
 15. The system ofclaim 10, wherein the moiety that comprises a reactive group comprises ahydrolysable diester.
 16. The system of claim 10, wherein the devicecomprising a multi-lumen catheter.
 17. The system of claim 10, whereinthe device further comprises a mixing section having a first mixingsection inlet in fluid communication with a distal end of a first lumen,a second mixing section inlet in fluid communication with a distal endof a second lumen, and a mixing section outlet.